Lung cancer is an increasingly common cause of cancer-related death in the world, and over 90% of deaths from lung cancer can be attributed to metastasis (Yano, S. et al., Int. J. Cancer 67:211-217, 1996). Lung cancer is histologically classified into two groups, small cell carcinoma (SCLC) and non-small cell carcinoma (NSCLC), based on different clinical behavior (the rate of tumor growth, the pattern of tumor progression, the sensitivity to chemo- and radiotherapy). In both type, however, metastasis to the multiple organs are frequently observed at the time of the diagnosis. Bone, following the liver and brain, is the third most common organs of metastasis in lung cancer patients. In particular, bone metastasis causes various severe symptoms by inducing pathological fracture, compression of spinal cord, and hypercalcemia, and reduces the quality of life of the patients (Iguchi, H. et al., Cancer Res. 56:4040-4043, 1996). Though palliative radiotherapy is given to reduce the symptoms for patients with bone metastasis, novel therapeutic modality is necessary for these patients to improve their prognosis.
Recently much attention has been paid to develop bone metastasis model with human cancer cells in order to understand the molecular mechanism and to develop therapeutic modality. When cancer cells were injected through the intracardiac route in immunodeficient mice, melanoma (Arguello, F. et al., Cancer Res. 48:6876-6881, 1988; Nakai, M. et al., Cancer Res. 52:5395-5399, 1988), breast cancer (Hall, D. G. and Stocia, G., J. Bone Miner. Res. 9:221-230, 1994; Sasaki, A. et al., Cancer Res. 55:3551-3557, 1995), prostate cancer (Shevrin, D. H. et al., Prostate 19:149-154, 1991), and lung cancer (Iguchi, H. et al., Cancer Res. 56:4040-4043, 1996) have been reported to produce bone metastasis.
In these models, tumor cells were inoculated into left ventricle of the heart and bone metastasis was developed in 75% recipient mice. However, intracardiac inoculation of tumor cells does not seem to be technically easy, and is associated with sudden death to some extent. Therefore, intracardiac injection of tumor cells imposes a lot of burden on animals, causing an ethical and economic problems.